Johns Hopkins School of Medicine

Molecular and Cellular Regulation of Neural Plasticity

Even among similar cell types, differences in synaptic connectivity and activity patterns render these populations functionally and molecularly distinct. While early cell type-specific investigations obtained molecular profiles on the basisof cell type markers,   molecular genetic tools now allow researchers to target circuits of interest with high precision based on connectivity as well as neural activity patterns in animal models. While animal models have made progress in identifying some of  the neural substrates underlying neuropsychiatric disorders, they cannot recapitulate all aspects of human disease. Towards better understanding the molecular pathology of complex brain disorders, large-scale efforts are underway to characterize the human brain transcriptome within and across cell types of the human brain. For example, single nucleus RNA-sequencing approaches have identified cell type-specific transcriptional changes in depression, Alzheimer’s disease, autism spectrum disorder and schizophrenia, and other analyses have identified cell type-specificenrichment of genetic risk. Our laboratory’s approach couples the power of circuit manipulation, molecular profiling  and activity-mapping in mouse models of behavior with transcriptomic approaches in the postmortem human brain to better understand how programs of gene expression in defined populations of cells contribute to circuit function and control of behaviors that are relevant for neuropsychiatric disorders. These studies provide novel approaches for defining the topography of gene expression in the rodent and human brain to better understand molecular mechanisms underlying psychiatric disorders. Specifically, we have developed novel approaches for revealing molecular profiles of distinct cell types within the intact tissue architecture using single-cell and spatially-resolved transcriptomics in the human brain, particularly in difficult to access regions, as well as executed large-scale case/control bulk RNA-sequencing studies. Our team is a leader in openly sharing data, but also in generating and providing user-friendly and widely-accessible tools to explore the data. For example, we have created interactive dashboards and web applications to explore single nucleus and spatially-resolved data in the human brain. Current directions in our laboratory take a cross-species approach to study how programs of gene expression in cell type- and circuit-specific neuronal populations contribute to circuit function and control of behaviors that are relevant for neuropsychiatric disorders. We use genetic manipulation and viral transgenesis in combination with molecular, cellular and systems-level recording techniques in animals, and integrate these data with cell type-specific and spatially-resolved transcriptomic data that we generate in the postmortem human brain. This integrated cross-species research program allows us to rapidly take molecular and genetic associations that we identify in the human brain for testing causality and function in circuit and behavioral models that are relevant for disease, and prioritize them for development of novel molecular therapeutics. Hence, promising molecular or cellular associations of disease identified in these studies can be rapidly reverse-translated to contextualize, explore and test causality in animal models.